The overall purpose of the Genetic Core unit, is to assist each of the three component TMRC projects with genetic studies. The specific aim of the Core is to identify genes and variants of these genes that play an important role in susceptibility or resistance to clinical malaria. The Core Unit will combine genetic studies of phenotypic variations related to malaria infection and functional analysis of the genes identified. These genes of variant(s) of genes may be involved in regulating immune responses, parasite invasion, growth and development within red blood cells or pathophysiological mechanisms of the disease. The knowledge obtained from these studies will therefore help in developing new therapeutic intervention for both prevention and treatment. Two genetic approaches will be used with Projects 1 to 3: genome-wide screening and a candidate genes approach. Genome-wide screening and linkage analysis of the families will localize the genes to a subchromosomal location by scanning the whole human genome. Fine genetic mapping by association studies will be performed using more polymorphic markers in the region to narrow it down. Genes located in the region will be identified and investigated for their function and tissue expression in order to identify potential candidate genes. These genes will be screened for the changes in the DNA sequence. The variants of these genes will be used in association studies in order to identify the variants, which show strong association. Functional analysis of these variants will be performed in order to identify the variant involved in the biological mechanisms. Candidate genes will be selected based on the studies in other populations or their known biological functions. If possible, the variants of these genes will be used for association studies and linkage analysis. If significant association is obtained, all variants of the genes including their regulatory regions will be identified systematically. Association studies using all these variants will e performed to identify the variant(s) showing strong association. Finally, the functional significance of these variants will be determined.